Converging lines of evidence have highlighted the involvement of ApoE and lipoprotein receptors in the pathogenesis of sporadic Alzheimer's disease (AD). In this project, we capitalize on our recent discovery that LR11/SorLA, a novel ApoE receptor, is downregulated in AD brain, to test the hypothesis LR11 plays an early role in AD progression. This hypothesis is supported by data from us and others demonstrating that LR11: interacts with IS-amyloid precursor protein (APR), regulates APR intracellular traffic, and modulates Ad production. Based on these findings, lower levels of LR11, as occurs selectively in vulnerable neurons in AD brain, would be predicted to contribute to amyloidogenesis. The Program Project entitled "Neurobiology of Mild Cognitive Impairment in the Elderly" provides an outstanding opportunity to further investigate the role of LR11 in AD pathogenesis. Our exciting preliminary studies demonstrate early changes in LR11 expression in a subset of mild cognitive impairment (MCI) cases, as well as unanticipated changes in basal forebrain neurons, and potential differences among ApoE genotypes. To extend these results as part of the program project, we will first evaluate LR11 expression across control, MCI, and AD brains, capitalizing on the wealth of collected data to assess clinicopathological and genotype correlations. Studies will also explore potential mechanisms of action of LR1T in AD brain by pursuing collaborative interactions with the other projects to evaluate links between LR11 and A(J and early neurodegenerative changes in cholinergic basal forebrain neurons. Our central hypothesis is that decreased expression and altered distribution of LR1.1 are early changes that contribute to the pathogenesis of AD. This hypothesis will be tested in the following specific aims: 1) To test the hypothesis that LR11 expression in vulnerable regions of cerebral cortex is progressively reduced in MCI and early AD vs. control brains;2) To test the hypothesis that LR11 levels are inversely linked to AB levels and amyloid burden in MCI;and 3) To test the hypothesis that LR11 is enriched in cholinergic basal forebrain neurons and that alterations in LR11 expression are correlated with progressive cholinergic dysfunction in control, MCI, and AD brains. The findings will provide new insights into the role of LR11 in AD pathogenesis, and the results may identify LR11 as a new target for AD therapeutics.